Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide and is increasing as emerging countries develop technology to save preterm infants but lack resources to provide optimal care. In the U.S.,˜14% of childhood blindness is attributed to ROP and in some developing nations, estimates are>20%. ROP is characterized by two phases based on clinical observations and animal models. In Phase I ROP, mainly peripheral avascular retina occurs from a delay in physiologic retinal vascular development (PRVD) and, in places with insufficient resources to regulate oxygen, hyperoxia-induced vaso-attenuation. In Phase II ROP, hypoxia-induced intravitreal neovascularization (IVNV) occurs. Treatments of IVNV in human severe ROP include laser ablation of peripheral avascular retina, which destroys developing retina, or intravitreal anti-VEGF agents, which can lead to persistent avascular retina, recurrent IVNV, and even blindness from retinal detachment. Intravitreal anti-VEGF agents reduce serum VEGF levels for weeks in human preterm infants and inhibit postnatal growth in pups in a rat model of ROP raising additional safety concerns. Some experimental methods to promote PRVD (e.g. insulin-like growth factor-1 or erythropoietin [EPO]) can worsen Phase II IVNV, whereas agents to inhibit IVNV (e.g. anti-VEGF) can cause persistent avascular retina, a stimulus for later IVNV. Therefore, the strategy for ROP in these fragile preterm infants is to understand mechanisms that allow for targeting specific cells and regulating signaling events involved in IVNV without interfering with PRVD.